Click-type Reaction Research Articles

A dynamic duo: pairing click chemistry and postpolymerization modification to design complex surfaces.

Advances in key 21st century technologies such as biosensors, biomedical implants, and organic light-emitting diodes rely heavily on our ability to imagine, design, and understand spatially complex interfaces. Polymer-based thin films provide many advantages in this regard, but the direct synthesis of polymers with incompatible functional groups is extremely difficult. Using postpolymerization modification in conjunction with click chemistry can circumvent this limitation and result in multicomponent surfaces that are otherwise unattainable. The two methods used to form polymer thin films include physisorption and chemisorption. Physisorbed polymers suffer from instability because of the weak intermolecular forces between the film and the substrate, which can lead to dewetting, delamination, desorption, or displacement. Covalent immobilization of polymers to surfaces through either a "grafting to" or "grafting from" approach provides thin films that are more robust and less prone to degradation. The grafting to technique consists of adsorbing a polymer containing at least one reactive group along the backbone to form a covalent bond with a complementary surface functionality. Grafting from involves polymerization directly from the surface, in which the polymer chains deviate from their native conformation in solution and stretch away from the surface because of the high density of chains. Postpolymerization modification (PPM) is a strategy used by our groups over the past several years to immobilize two or more different chemical functionalities onto substrates that contain covalently grafted polymer films. PPM exploits monomers with reactive pendant groups that are stable under the polymerization conditions but are readily modified via covalent attachment of the desired functionality. "Click-like" reactions are the most common type of reactions used for PPM because they are orthogonal, high-yielding, and rapid. Some of these reactions include thiol-based additions, activated ester coupling, azide-alkyne cycloadditions, some Diels-Alder reactions, and non-aldol carbonyl chemistry such as oxime, hydrazone, and amide formation. In this Account, we highlight our research combining PPM and click chemistry to generate complexity in polymer thin films. For the purpose of this Account, we define a complex coating as a polymer film grafted to a planar surface that acts as a template for the patterning of two or more discrete chemical functionalities using PPM. After a brief introduction to grafting, the rest of the review is arranged in terms of the sequence in which PPM is performed. First, we describe sequential functionalization using iterations of the same click-type reaction. Next, we discuss the use of two or more different click-like reactions performed consecutively, and we conclude with examples of self-sorting reactions involving orthogonal chemistries used for one-pot surface patterning.

Polyglycidol-Based Prepolymers to Tune the Nanostructure of Microgels

The use of prepolymers for microgel synthesis via miniemulsification allows predefining the chemical functionality and the nanostructure of microgels. We report on tailor-made polyglycidol-based prepolymers using three protected glycidol monomers (allyl glycidyl ether, AGE; ethoxy ethyl glycidyl ether, EEGE; and tert-butyl glycidyl ether, tBGE). AGE with its pendant double bonds serves as site for cross-linking or functionalization, whereas the EEGE and tBGE building blocks represent precursors for hydroxyl functionalities. Following the prepolymer approach, we design statistical and block copolymers to control the nanostructure of the microgel. Cross-linking of the prepolymers is achieved in miniemulsions under UV irradiation in a thiol–ene click type reaction addressing the allyl groups with 2,2′-(ethylenedioxy)diethanethiol. Analysis with cryo-TEM reveals that microgels derived from poly(glycidol)-block-poly(AGE) show larger hydrophobic domains than microgels derived from statistical copolymers. Additionally, the cross-linking of pH responsive tBGE/AGE prepolymers with different microstructures leads to microgels with nanostructures differing in local charge distributions.

Superstructures of fluorescent cyclodextrin via click-reaction

Mono-(6-azido-6-deoxy)-β-cyclodextrin (CD) was covalently attached to an alkyne-modified 5-methyl-2-(pyridin-2-yl)thiazol-4-ol yielding a fluorophore containing CD in a click-type reaction. Intermolecular complexes were formed by poly(host–guest)-interactions. The supramolecular structures were characterized by 1H NMR-ROESY spectroscopy, dynamic light scattering, UV–vis spectroscopy, fluorescence spectroscopy, and asymmetric flow field-flow fractionation. By adding potassium adamantane-1-carboxylate, the thiazol dye is displaced from the CD-cavity and the elongated noncovalent polymeric structures collapse.

Catechol-Initiated Polyethers: Multifunctional Hydrophilic Ligands for PEGylation and Functionalization of Metal Oxide Nanoparticles

Bifunctional CA-PEG (catechol-poly(ethylene glycol)) and multifunctional CA-PEG-PGA/PEVGE (poly(glycidyl amine)/poly(ethylene glycol vinyl glycidyl ether)) ligands for the functionalization and solubilization of nanoparticles are introduced. Tunable polymers with polydispersities <1.25 and molecular weights in the range 500-7700 g mol(-1) containing a catechol moiety for conjugation to metal oxide nanoparticles were prepared. The functional PEG ligands were synthesized starting from the acetonide-protected catechol initiator 2,2-dimethyl-1,3-benzodioxole-5-propanol (CA-OH) for oxyanionic polymerization. CA-OH was used both for homopolymerization of ethylene oxide (EO) as well as copolymerization with functional epoxides N,N-diallyl glycidyl amine (DAGA), releasing primary amino groups and ethylene glycol vinyl glycidyl ether (EVGE), exhibiting a double bond for click-type reactions, to generate CA-PEG and CA-PEG-PGA/PEVGE. We demonstrate the potential of the functional ligands by binding to MnO nanoparticles, rendering the PEGylated nanoparticles highly stable in aqueous environment. Furthermore, addressability of the functional groups has been proven, for example, by coupling with fluoresceine isothiocyanate (FITC), to allow for optical monitoring of the nanoparticle fate in biological systems.

Easy and effective method to produce functionalized particles for cellular uptake

In this contribution, a versatile approach for the synthesis of functionalized particles for drug delivery is presented, using two nonaggressive standardized procedures. The first procedure considered is the functionalization of an azido-terminated α-norbornenyl poly(ethylene oxide) (PEO) macromonomer with an alkyne-containing active molecule via the copper catalyzed azide alkyne cycloaddition, click type reaction. The functionalized macromonomer is then polymerized by Ring-Opening Metathesis Polymerization (ROMP) in dispersion to form functionalized particles. The second procedure consists in synthesizing particles by ROMP in dispersed media of norbornene with azido-terminated α-norbornenyl PEO macromonomer. The ROMP was initiated by the first generation Grubbs catalyst. Such functionalized core-shell particles have stealthy properties due to their PEO shell and can be viewed as universal nanocarriers on which any alkyne-modified active molecule can be grafted by click chemistry. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2013

Surface Patterning by Microcontact Chemistry

In this Feature Article we describe recent progress in covalent surface patterning by microcontact chemistry. Microcontact chemistry is a variation of microcontact printing based on the transfer of reactive "ink" molecules from a microstructured, elastomeric stamp onto surfaces modified with complementary reactive groups, leading to a chemical reaction in the area of contact. In comparison with other lithographic methods, microcontact chemistry has a number of advantageous properties including very short patterning times, low consumption of ink molecules, high resolution and large area patterning. During the past 5 years we and many others have investigated a set of different reactions that allow the modification of flat and also spherical surfaces in an effective way. Especially click-type reactions were found to be versatile for substrate patterning by microcontact chemistry and were applied for chemical modification of reactive self-assembled monolayers and polymer surfaces. Microcontact chemistry has already found broad application for the production of functional surfaces and was also used for the preparation of DNA, RNA, and carbohydrate microarrays, for the immobilization of proteins and cells and for the development of sensors.

PEG-based Multifunctional Polyethers with Highly Reactive Vinyl-Ether Side Chains for Click-Type Functionalization

Introduction of highly reactive vinyl ether moieties along a poly(ethylene glycol) (PEG) backbone has been realized by copolymerization of the novel epoxide monomer ethoxy vinyl glycidyl ether (EVGE) with ethylene oxide (EO). A series of copolymers with varying structure (block and random) as well as EVGE comonomer content (5–100%) with molecular weights in the range of 3,900–13,200 g/mol and narrow molecular weight distributions (Mw/Mn = 1.06–1.20) has been synthesized and characterized with respect to their microstructure and thermal properties. The facile transformation of the vinyl ether side chains in click type reactions was verified by two different post polymerization modification reactions: (i) thiol–ene addition and (ii) acetal formation, employing various model compounds. Both strategies are very efficient, resulting in quantitative conversion. The rapid and complete acetal formation with alcohols results in an acid-labile bond and is thus highly interesting with respect to biomedical applicati...

DNA or RNA Oligonucleotide 2′-Hydrazides for Chemoselective Click-Type Ligation with Carbonyl Compounds

An efficient method for the synthesis of DNA or RNA oligonucleotide 2′-hydrazides is described. Fully deprotected oligonucleotides containing a hydrazide group at the 2′-position of a uridine residue were obtained by a novel two-step procedure: periodate cleavage of an oligonucleotide with 1,2-diol group followed by conversion of the aldehyde to hydrazide with an extended linker arm using a homobifunctional reagent succinic dihydrazide and NaBH3CN. The resulting oligonucleotide 2′-hydrazides were efficiently conjugated by a click-type reaction at acidic pH to aliphatic or aromatic aldehydes with or without NaBH3CN reduction to afford novel 2′-conjugates.

General Method for Labeling siRNA by Click Chemistry with Fluorine-18 for the Purpose of PET Imaging

The alkyne-azide Cu(I)-catalyzed Huisgen cycloaddition, a click-type reaction, was used to label a double-stranded oligonucleotide (siRNA) with fluorine-18. An alkyne solid support CPG for the preparation of monostranded oligonucleotides functionalized with alkyne has been developed. Two complementary azide labeling agents (1-(azidomethyl)-4-[(18)F]fluorobenzene) and 1-azido-4-(3-[(18)F]fluoropropoxy)benzene have been produced with 41% and 35% radiochemical yields (decay-corrected), respectively. After annealing with the complementary strand, the siRNA was directly labeled by click chemistry with [(18)F]fluoroazide to produce the [(18)F]-radiolabeled siRNA with excellent radiochemical yield and purity.

Remarkable high-yielding chemical modification of gold nanoparticles using uncatalyzed click-type 1,3-dipolar cycloaddition chemistry and hyperbaric conditions

Azide-terminated alkyl thiolate monolayer-protected gold nanoparticles (1-C12MPN) with a core size of 1.8 ± 0.2 nm were prepared. 1-C12MPN was modified in high yields via an uncatalyzed 1,3-dipolar cycloaddition (click-type reaction) with a variety of terminal acyl–alkynes under hyperbaric conditions at 11 000 atm. The resulting 1,2,3-triazole modified MPNs (2-C12MPN) were characterized using 1H NMR spectroscopy and were verified by comparison of the spectra to those obtained for the products of the model reactions of 1-azidododecane with the same alkynes. TEM analysis showed that the high-pressure conditions did not affect the size of the gold core, suggesting that the only effect is to facilitate the chemical reaction on the particles.

New Strategy for the Preparation of Clickable Peptides and Labeling with 1-(Azidomethyl)-4-[18F]-fluorobenzene for PET

The alkyne-azide Cu(I)-catalyzed Huisgen cycloaddition, a click type reaction was used to label a peptide with fluorine-18. A novel solid phase synthesis approach for the preparation of clickable peptides has been developed and has also permitted the straightforward preparation of reference compounds. A complementary azide labeling agent (1-(azidomethyl)-4-[(18)F]-fluorobenzene) has been produced in a four step procedure in 75 min with a 34% radiochemical yield (decay corrected). Conjugation of [(18)F]fluoroazide with a model alkyne-neuropeptide produced the desired (18)F-radiolabeled peptide in less than 15 min with a yield of 90% and excellent radiochemical purity.

The Emergence of Thiol–Ene Coupling as a Click Process for Materials and Bioorganic Chemistry

The century-old thiol–ene radical reaction is now being recognized among the ranks of other click-type reactions (see scheme). Recent applications in dendrimer and glycopeptide syntheses demonstrate the efficiency of this process for the assembly of complex molecular systems.

Click-Type Reaction of Aromatic Polyamines for Improvement of Thermal and Optoelectronic Properties

A quantitative addition reaction between aromatic amino-substituted alkynes and tetracyanoethylene (TCNE), yielding donor-substituted tetracyanobutadiene chromophores, was for the first time employed as a click-type reaction to improve the thermal and optoelectronic properties of aromatic polyamines. The first reduction potentials or the LUMO levels of the aromatic polyamines were found to linearly decrease by the stepwise TCNE addition.

Layer‐by‐Layer Assembly of Reactive Ultrathin Films Mediated by Click‐Type Reactions of Poly(2‐Alkenyl Azlactone)s

Covalently crosslinked ultrathin films can be fabricated layer-by-layer by exploiting fast and efficient click-type reactions between polyamines and the ‘spring-loaded' functionality of poly(2-alkenyl azlactone)s. The accessibility and reactivity of residual azlactone functionality in these ultrathin materials permits further functionalization post-fabrication, suggesting new approaches to the modification, passivation, or patterning of curved or topologically complex surfaces with chemical or biological functionality. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2089/2007/c0822_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Graft Copolymers by a Combination of ATRP and Two Different Consecutive Click Reactions

The epoxide ring in glycidyl butyrate (model compound) and in well-defined copolymers of glycidyl methacrylate (<40 mol %) and methyl methacrylate prepared by ATRP was efficiently opened with sodium azide in the presence of ammonium chloride in DMF at 50 °C. This click-type reaction led to the formation of the corresponding 1-hydroxy-2-azido compounds in high yields. The prepared azide-containing copolymers were functionalized in a second click reaction, the room temperature CuBr/N,N,N‘,N‘ ‘,N‘ ‘-pentamethyldiethylenetriamine-catalyzed 1,3-dipolar cycloaddition, of poly(ethylene oxide) methyl ether pentynoate to yield loosely grafted polymeric brushes with hydrophilic PEO side chains.